It has been becoming clear that each organ or tissue in the living organism has tissue stem cells that maintain its structural and functional homeostasis. For example, cardiac stem cells are present in the heart, neural stem cells are present in the brain, and epidermal stem cells and hair follicle stem cells are present in the skin. They provide cardiomyocytes, neurons, and epidermal cells and hair follicle epithelial cells to the heart, brain, and skin, respectively, over a lifetime to maintain their structures and functions. Meanwhile, hematopoietic stem cells, which differentiate into blood cells such as erythrocytes, leukocytes, and platelets, are present in the bone marrow. The blood cells derived from hematopoietic stem cells circulate through all organs or tissues in the body via blood flow and serve essential functions for the maintenance of life, such as oxygen supply, immune response, arrest of hemorrhage, and repair of damaged tissues. Thus, it is fair to say that bone-marrow hematopoietic stem cells contribute to maintaining the homeostasis of all tissues in the body via peripheral circulation, rather than maintaining the homeostasis of bone marrow and bone tissues where they are localized.
Recently, it has been demonstrated that, in addition to hematopoietic stem cells, mesenchymal stem cells capable of differentiating into not only mesodermal tissues such as bone, cartilage, and adipose but also ectodermal tissues such as neuron and epidermis are present in the bone marrow. However, little is understood about the significance of the presence of mesenchymal stem cells in the living body. However, given that hematopoietic stem cells that maintain the homeostasis of all organs and tissues by supplying blood cells via peripheral circulation are present in the bone marrow, it is expected that mesenchymal stem cells present in the bone marrow may also contribute to the homeostatic maintenance of living tissues by supplying cells capable of differentiating into bone, cartilage, adipose, neuron, epithelium, etc., to tissues or organs in need thereof in the living body via peripheral circulation.
Currently, regenerative medicine is under intensive development, in which bone marrow mesenchymal stem cells are prepared by collecting bone-marrow blood, and after expansion by cell culture, the cells are grafted into the site of intractable tissue damage or into peripheral circulation to induce regeneration of the damaged tissue. Clinical application of bone marrow mesenchymal stem cell transplantation has already been underway in regenerative medicine for cerebral infarction, cardiac infarction, intractable skin ulcer, etc. Furthermore, transplanted bone marrow mesenchymal stem cells have been demonstrated to produce the effect of suppressing inflammation and immune response as well as the effect of suppressing fibrous scar formation at local sites in the body. Clinical trials have begun on bone marrow mesenchymal stem cell transplantation therapy as a new therapeutic method to treat scleroderma, which is an autoimmune disease, or to treat graft versus host disease (GVHD), which is a serious side effect after bone marrow transplantation or blood infusion. However, bone-marrow blood containing bone marrow mesenchymal stem cells is collected only by an invasive method where thick needles are repeatedly inserted into the iliac bone. In addition, continuous passages of bone marrow mesenchymal stem cells outside the body lead to gradual loss of their proliferative ability and multipotency. Moreover, since culturing bone marrow mesenchymal stem cells with high quality control for ensuring the safety of in vivo transplantation requires special cell culture facilities such as cell processing center (CPC), it can only be performed currently in very limited universities and companies. Thus, in order to make the regenerative medicine using bone marrow mesenchymal stem cells available to a large number of patients around the world suffering from intractable tissue damage, it is an urgent task to develop techniques for mesenchymal stem cell regenerative medicine that can be performed in any medical facilities.
High mobility group box 1 (HMGB1) protein was identified about 30 years ago as a non-histone chromatin protein that regulates gene expression and DNA repair by regulating the structure of nuclear chromatin. The structure of the HMGB1 protein is primarily constituted by two DNA-binding domains, and those at the N- and C-terminal are referred to as A-box and B-box, respectively. Past studies have revealed that the domain which binds TLR to induce inflammatory reaction is located within the B-box of the HMGB1 molecule.